ed with nsaid use. the concurrent use of aspirin and an nsaid does increase the risk of serious gi events (see warnings: gastrointestinal effects - risk of ulceration, bleeding, and perforation). two large, controlled, clinical trials of a cox-2 selective nsaid for the treatment of pain in the first 10 to 14 days following cabg surgery found an increased incidence of myocardial infarction and stroke (see contraindications). hypertension nsaids, including naproxen tablets, can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of cv events. patients taking thiazides or loop diuretics may have impaired response to these therapies when taking nsaids. nsaids, including naproxen tablets, should be used with caution in patients with hypertension. blood pressure (bp) should be monitored closely during the initiation of nsaid treatment and throughout the course of therapy. congestive heart failure and edema fluid retention, edema, and peripheral edema have been observed in some patients taking nsaids. naproxen tablets should be used with caution in patients with fluid retention, hypertension, or heart failure. gastrointestinal effects- risk of ulceration, bleeding, and perforation nsaids, including naproxen tablets, can cause serious gastrointestinal (gi) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. these serious adverse events can occur at any time, with or without warning symptoms, in patients treated with nsaids. only one in five patients, who develop a serious upper gi adverse event on nsaid therapy, is symptomatic. upper gi ulcers, gross bleeding, or perforation caused by nsaids occur in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for one year. these trends continue with longer duration of use, increasing the likelihood of developing a serious gi event at some time during the course of therapy. however, even short-term therapy is not without risk. the utility of periodic laboratory monitoring has not been demonstrated, nor has it been adequately assessed. only 1 in 5 patients who develop a serious gi adverse event on nsaid therapy is symptomatic. nsaids should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use nsaids have a greater than 10-fold increased risk for developing a gi bleed compared to patients with neither of these risk factors. other factors that increase the risk for gi bleeding in patients treated with nsaids include concomitant use of oral corticosteroids or anticoagulants, longer duration of nsaid therapy, smoking, use of alcohol, older age, and poor general health status. most spontaneous reports of fatal gi events are in elderly or debilitated patients and therefore, special care should be taken in treating this population. to minimize the potential risk for an adverse gi event in patients treated with an nsaid, the lowest effective dose should be used for the shortest possible duration. patients and physicians should remain alert for signs and symptoms of gi ulceration and bleeding during nsaid therapy and promptly initiate additional evaluation and treatment if a serious gi adverse event is suspected. this should include discontinuation of the nsaid until a serious gi adverse event is ruled out. for high risk patients, alternate therapies that do not involve nsaids should be considered. epidemiological studies, both of the case-control and cohort design, have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. in two studies, concurrent use of an nsaid or aspirin potentiated the risk of bleeding (see precautions: drug interactions). although these studies focused on upper gastrointestinal bleeding, there is no reason to believe that bleeding at other sites may be similarly potentiated. nsaids should be given with care to patients with a history of inflammatory bowel disease (ulcerative colitis, crohn’s disease) as their condition may be exacerbated. renal effects long-term administration of nsaids has resulted in renal papillary necrosis and other renal injury. renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. in these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. patients at greatest risk of this reaction are those with impaired renal function, hypovolemia, heart failure, liver dysfunction, salt depletion, those taking diuretics and angiotensin converting enzyme (ace) inhibitors or angiotensin receptor blockers (arbs), and the elderly. discontinuation of nonsteroidal anti-inflammatory drug therapy is usually followed by recovery to the pretreatment state (see warnings: advanced renal disease). advanced renal disease no information is available from controlled clinical studies regarding the use of naproxen tablets in patients with advanced renal disease. therefore, treatment with naproxen tablets is not recommended in these patients with advanced renal disease. if naproxen tablets therapy must be initiated, close monitoring of the patient’s renal function is advisable and patients should be adequately hydrated. anaphylactoid reactions as with other nsaids, anaphylactoid reactions may occur in patients without known prior exposure to naproxen tablets. naproxen tablets should not be given to patients with the aspirin triad. this symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other nsaids (see contraindications and precautions: preexisting asthma). emergency help should be sought in cases where an anaphylactoid reaction occurs. anaphylactoid reactions, like anaphylaxis, may have a fatal outcome. skin reactions nsaids, including naproxen tablets, can cause serious skin adverse events such as exfoliative dermatitis, stevens-johnson syndrome (sjs), and toxic epidermal necrolysis (ten), which can be fatal. these serious events may occur without warning. patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity. pregnancy in late pregnancy, as with other nsaids, naproxen tablets should be avoided because it may cause premature closure of the ductus arteriosus.

erapy is to choose a formulation and a starting dose likely to be effective for the patient and then adjust the dosage based on observation of benefit and/or adverse events. a lower dose should be considered in patients with renal or hepatic impairment or in elderly patients (see warnings and precautions). geriatric patients studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. caution is advised when high doses are required and some adjustment of dosage may be required in elderly patients. as with other drugs used in the elderly, it is prudent to use the lowest effective dose. patients with moderate to severe renal impairment naproxen-containing products are not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance <30 ml/min) (see warnings: renal effects). rheumatoid arthritis, osteoarthritis and ankylosing spondylitis naproxen tablets, usp 250 mg or 375 mg or 500 mg twice daily twice daily twice daily during long-term administration, the dose of naproxen may be adjusted up or down depending on the clinical response of the patient. a lower daily dose may suffice for long-term administration. the morning and evening doses do not have to be equal in size and the administration of the drug more frequently than twice daily is not necessary. in patients who tolerate lower doses well, the dose may be increased to naproxen 1500 mg/day for limited periods of up to 6 months when a higher level of anti-inflammatory/ analgesic activity is required. when treating such patients with naproxen 1500 mg/day, the physician should observe sufficient increased clinical benefits to offset the potential increased risk. the morning and evening doses do not have to be equal in size and administration of the drug more frequently than twice daily does not generally make a difference in response (see clinical pharmacology). acute gout the recommended starting dose is 750 mg of naproxen tablets, usp followed by 250 mg every 8 hours until the attack has subsided.

ere about the same, and the incidence of other reactions were lower in pediatric patients than in adults. in patients taking naproxen in clinical trials, the most frequently reported adverse experiences in approximately 1% to 10% of patients are: gastrointestinal (gi) experiences, including: heartburn*, abdominal pain*, nausea*, constipation*, diarrhea, dyspepsia, stomatitis central nervous system: headache*, dizziness*, drowsiness*, lightheadedness, vertigo dermatologic: pruritus (itching)*, skin eruptions*, ecchymoses*, sweating, purpura special senses: tinnitus*, visual disturbances, hearing disturbances cardiovascular: edema*, palpitations. general: dyspnea*, thirst *incidence of reported reaction between 3% and 9%. those reactions occurring in less than 3% of the patients are unmarked. in patients taking nsaids, the following adverse experiences have also been reported in approximately 1% to 10% of patients. gastrointestinal (gi) experiences, including: flatulence, gross bleeding/perforation, gi ulcers (gastric/duodenal), vomiting general: abnormal renal function, anemia, elevated liver enzymes, increased bleeding time, rashes the following are additional adverse experiences reported in <1% of patients taking naproxen during clinical trials and through postmarketing reports. those adverse reactions observed through postmarketing reports are italicized. body as a whole: anaphylactoid reactions, angioneurotic edema, menstrual disorders, pyrexia (chills and fever) cardiovascular: congestive heart failure, vasculitis, hypertension, pulmonary edema gastrointestinal:inflammation, bleeding(sometimes fatal, particularly in the elderly), ulceration, perforation and obstruction of the upper and lower gastrointestinal tract. esophagitis, stomatitis, hematemesis, pancreatitis, vomiting, colitis, exacerbation of inflammatory bowel disease (ulcerative colitis, crohn’s disease). hepatobiliary: jaundice, abnormal liver function tests, hepatitis (some cases have been fatal) hemic and lymphatic:eosinophilia, leucopenia, melena, thrombocytopenia, agranulocytosis, granulocytopenia, hemolytic anemia, aplastic anemia metabolic and nutritional:hyperglycemia, hypoglycemia nervous system: inability to concentrate, depression, dream abnormalities, insomnia, malaise, myalgia, muscle weakness, aseptic meningitis, cognitive dysfunction, convulsions respiratory:eosinophilic pneumonitis, asthma dermatologic: alopecia, urticaria, skin rashes, toxic epidermal necrolysis, erythema multiforme, erythema nodosum, fixed drug eruption, lichen planus, pustular reaction, systemic lupus erythematosus, bullous reactions, including stevens-johnson syndrome, photosensitive dermatitis, photosensitivity reactions, including rare cases resembling porphyria cutanea tarda (pseudoporphyria) or epidermolysis bullosa. if skin fragility, blistering or other symptoms suggestive of pseudoporphyria occur, treatment should be discontinued and the patient monitored. special senses:hearing impairment, corneal opacity, papillitis, retrobulbar optic neuritis, papilledema urogenital:glomerular nephritis, hematuria, hyperkalemia, interstitial nephritis, nephrotic syndrome, renal disease, renal failure, renal papillary necrosis, raised serum creatinine reproduction (female):infertility in patients taking nsaids, the following adverse experiences have also been reported in <1% of patients. body as a whole: fever infection, sepsis, anaphylactic reactions, appetite changes, death cardiovascular: hypertension, tachycardia, syncope, arrhythmia, hypotension, myocardial infarction gastrointestinal: dry mouth, esophagitis, gastric/peptic ulcers, gastritis, glossitis, eructation hepatobiliary: hepatitis, liver failure hemic and lymphatic: rectal bleeding, lymphadenopathy, pancytopenia metabolic and nutritional: weight changes nervous system: anxiety, asthenia, confusion, nervousness, paresthesia, somnolence, tremors, convulsions, coma, hallucinations respiratory: asthma, respiratory depression, pneumonia dermatologic: exfoliative dermatitis special senses: blurred vision, conjunctivitis urogenital: cystitis, dysuria, oliguria/polyuria, proteinuria

n is consistent with this half-life. this suggests that the differences in pattern of release play only a negligible role in the attainment of steady-state plasma levels. absorption immediate release after administration of naproxen tablets, peak plasma levels are attained in 2 to 4 hours. distribution naproxen has a volume of distribution of 0.16 l/kg. at therapeutic levels naproxen is greater than 99% albumin-bound. at doses of naproxen greater than 500 mg/day there is less than proportional increase in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher doses (average trough css 36.5, 49.2, and 56.4 mg/l with 500, 1000 and 1500 mg daily doses of naproxen, respectively). the naproxen anion has been found in milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma (see precautions: nursing mothers). metabolism naproxen is extensively metabolized in the liver to 6-0-desmethyl naproxen, and both parent and metabolites do not induce metabolizing enzymes. both naproxen and 6-0-desmethyl naproxen are further metabolized to their respective acylglucuronide conjugated metabolites. excretion the clearance of naproxen is 0.13 ml/min/kg. approximately 95% of the naproxen from any dose is excreted in the urine, primarily as naproxen (<1%), 6-0-desmethyl naproxen (<1%) or their conjugates (66% to 92%). the plasma half-life of the naproxen anion in humans ranges from 12 to 17 hours. the corresponding half-lives of both naproxen’s metabolites and conjugates are shorter than 12 hours, and their rates of excretion have been found to coincide closely with the rate of naproxen disappearance from the plasma. small amounts, 3% or less of the administered dose, are excreted in the feces. in patients with renal failure metabolites may accumulate (see warnings: renal effects). special populations geriatric patients studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly, although the unbound fraction is < 1% of the total naproxen concentration. unbound trough naproxen concentrations in elderly subjects have been reported to range from 0.12% to 0.19% of total naproxen concentration, compared with 0.05% to 0.075% in younger subjects. the clinical significance of this finding is unclear, although it is possible that the increase in free naproxen concentration could be associated with an increase in the rate of adverse events per a given dosage in some elderly patients. race pharmacokinetic differences due to race have not been studied. hepatic insufficiency naproxen pharmacokinetics has not been determined in subjects with hepatic insufficiency. renal insufficiency naproxen pharmacokinetics has not been determined in subjects with renal insufficiency. given that naproxen, its metabolites and conjugates are primarily excreted by the kidney, the potential exists for naproxen metabolites to accumulate in the presence of renal insufficiency. elimination of naproxen is decreased in patients with severe renal impairment. naproxen-containing products are not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance <30 ml/min) (see warnings: renal effects).

standard formulations of naproxen 375 mg bid (750 mg/day) vs 750 mg bid (1500 mg/day), 9 patients in the 750 mg group terminated prematurely because of adverse events. nineteen patients in the 1500 mg group terminated prematurely because of adverse events. most of these adverse events were gastrointestinal events. in clinical studies in patients with rheumatoid arthritis, osteoarthritis, and juvenile arthritis, naproxen has been shown to be comparable to aspirin and indomethacin in controlling the aforementioned measures of disease activity, but the frequency and severity of the milder gastrointestinal adverse effects (nausea, dyspepsia, heartburn) and nervous system adverse effects (tinnitus, dizziness, lightheadedness) were less in naproxen-treated patients than in those treated with aspirin or indomethacin. in patients with ankylosing spondylitis, naproxen has been shown to decrease night pain, morning stiffness and pain at rest. in double-blind studies the drug was shown to be as effective as aspirin, but with fewer side effects. in patients with acute gout, a favorable response to naproxen was shown by significant clearing of inflammatory changes (e.g., decrease in swelling, heat) within 24 to 48 hours, as well as by relief of pain and tenderness. naproxen has been studied in patients with mild to moderate pain secondary to postoperative, orthopedic, postpartum episiotomy and uterine contraction pain and dysmenorrhea. onset of pain relief can begin within 1 hour in patients taking naproxen. analgesic effect was shown by such measures as reduction of pain intensity scores, increase in pain relief scores, decrease in numbers of patients requiring additional analgesic medication, and delay in time to remedication. the analgesic effect has been found to last for up to 12 hours. naproxen may be used safely in combination with gold salts and/or corticosteroids; however, in controlled clinical trials, when added to the regimen of patients receiving corticosteroids, it did not appear to cause greater improvement over that seen with corticosteroids alone. whether naproxen has a “steroid-sparing” effect has not been adequately studied. when added to the regimen of patients receiving gold salts, naproxen did result in greater improvement. its use in combination with salicylates is not recommended because there is evidence that aspirin increases the rate of excretion of naproxen and data are inadequate to demonstrate that naproxen and aspirin produce greater improvement over that achieved with aspirin alone. in addition, as with other nsaids, the combination may result in higher frequency of adverse events than demonstrated for either product alone. in 51cr blood loss and gastroscopy studies with normal volunteers, daily administration of 1000 mg of naproxen as 1000 mg of naproxen tablets has been demonstrated to cause statistically significantly less gastric bleeding and erosion than 3250 mg of aspirin. geriatric patients the hepatic and renal tolerability of long-term naproxen administration was studied in two double-blind clinical trials involving 586 patients. of the patients studied, 98 patients were age 65 and older and 10 of the 98 patients were age 75 and older. naproxen was administered at doses of 375 mg twice daily or 750 mg twice daily for up to 6 months. transient abnormalities of laboratory tests assessing hepatic and renal function were noted in some patients, although there were no differences noted in the occurrence of abnormal values among different age groups.

86°f) [see usp controlled room temperature]. dispense in well-closed, light-resistant containers as defined in the usp. rx only distributed by: amneal pharmaceuticals bridgewater, nj 08807 rev. 10-2015-01